In our renewal application we bring to fruition our successful developments of accurate compensation methods for physical factors affecting image quality and reconstruction approaches for quantitative dual isotope SPECT, and expand our scope to PET. We develop and assess the performance of quantitative dual isotope SPECT and PET in activity estimation tasks related to early diagnosis and quantitation of disease extent in coronary artery disease (CAD) and early Parkinson disease (PD) with or without dementia, and determine the best possible performance in these tasks. 1. We will develop novel scatter correction techniques for single and dual isotope PET and evaluate their performance in simulation and phantom data. 2. We will develop novel dual isotope brain PET and SPECT approaches and validate our methods in physical phantoms as well as animal and human studies. 3. we will develop novel dual tracer PET and SPECT cardiac methods and exvaluate their performance in phantoms, animal and human studies. In cardiac studies, we believe that our simultaneous protocol would yield stress and rest studies under identical conditions of patient motion, positioning, and attenuation paths, hence allowing accurate and robust estimation of the extent and severity of ischemia in CAD patients. This will be validated in a cohort of patients with intermediate risk of CAD. In brain studies, we believe that our dual isotope perfusion/DAT approach would yield insight into PD with or without dementia.